Donanemab in Early Symptomatic Alzheimer Disease
Authors: John R. Sims, Jennifer A. Zimmer, Cynthia D. Evans, Ming Lu, Paul Ardayfio, JonDavid Sparks, Alette M. Wessels, Sergey Shcherbinin, Hong Wang, Emel Serap Monkul Nery, Emily C. Collins, Paul Solomon, Stephen Salloway, Liana G. Apostolova, Oskar Hansson, Craig Ritchie, Dawn A. Brooks, Mark Mintun, Daniel M. Skovronsky, Rafael Abreu, Pinky Agarwal, Puja Aggarwal, Marc Agronin, Alison Allen, Dario Altamirano, Gustavo Alva, James Andersen, Allan Anderson, Donald Anderson, Jennifer Arnold, Takashi Asada, Yasuhiro Aso, Vikram Atit, Ricardo Ayala, Michael Badruddoja, Hanna Badzio-jagiello, Michal Bajacek, David Barton, David Bear, Sabrina Benjamin, Richard Bergeron, Perminder Bhatia, Sandra Black, Allan Block, Mohammad Bolouri, Wendy Bond, Jean Bouthillier, Sharon Brangman, Bruce Brew, Sarah Brisbin, Toby Brisken, Amy Brodtmann, Mark Brody, Jared Brosch, Celia Brown, Paul Brownstone, Sylwia Bukowczan, Jeffrey Burns, Alicia Cabrera, Horace Capote, Angel Carrasco, Jose Cevallos Yepez, Eric Chavez, Howard Chertkow, Urszula Chyrchel-paszkiewicz, Anthony Ciabarra, Edward Clemmons, Daniel Cohen, Robert Cohen, Ian Cohen, Mauricio Concha, Brian Costell, Denis Crimmins, Yvette Cruz-pagan, Adolfo Cueli, Robert Cupelo, Maciej Czarnecki, David Darby, P.l.j. Dautzenberg, Peter De Deyn, Jose De La Gandara, Kenneth Deck, David Dibenedetto, Mark Dibuono, Eric Dinnerstein, Ahmet Dirican, Shanker Dixit, Jacek Dobryniewski, Ryan Drake, Peter Drysdale, Ranjan Duara, John Duffy, Aaron Ellenbogen, Victor Faradji, Marc Feinberg, Robert Feldman, Simon Fishman, Stephen Flitman, Concetta Forchetti, Ivonne Fraga, Andrew Frank, Benjamin Frishberg, Hiroto Fujigasaki, Hiroyuki Fukase, Ileana Fumero, Kenichi Furihata, Christopher Galloway, Rekha Gandhi, Kristi George, Marcel Germain, Darren Gitelman, Nicholas Goetsch, Danielle Goldfarb, Mark Goldstein, Lawrence Goldstick, Yaneicy Gonzalez Rojas, Ira Goodman, David Greeley, Carl Griffin, Eric Grigsby, Daniel Grosz, Karl Hafner, David Hart, Sam Henein, Brad Herskowitz, Shinji Higashi, Yasuto Higashi, Gilbert Ho, Jonathan Hodgson, Mark Hohenberg, Larry Hollenbeck, Richard Holub, Tomokatsu Hori, Jakub Hort, Jan Ilkowski, K. Jennifer Ingram, Mitchell Isaac, Mitsunori Ishikawa, Lubos Janu, Mark Johnston, William Julio, William Justiz, Tomotsugu Kaga, Tatsuya Kakigi, Marvin Kalafer, Mikiko Kamijo, Jeffrey Kaplan, Michael Karathanos, Sadao Katayama, Siddharth Kaul, Andrew Keegan, Diana Kerwin, Uzma Khan, Arifulla Khan, Noriyuki Kimura, Gregory Kirk, Gabriela Klodowska, Hisatomo Kowa, Christen Kutz, Joseph Kwentus, Rosalyn Lai, Ayesha Lall, Mary Lawrence, Elly Lee, Ramon Leon, Gary Linker, Pawel Lisewski, Jonathan Liss, Collins Liu, Scott Losk, Ewelina Lukaszyk, Jennifer Lynch, Stephen Macfarlane, Josephine Macsweeney, Nicholas Mannering, Oto Markovic, Donald Marks, Joseph Masdeu, Yutaka Matsui, Kunitaka Matsuishi, Peter Mcallister, Brock Mcconnehey, Alvin Mcelveen, Lora Mcgill, Adam Mecca, Michael Mega, Jason Mensah, Anatol Mickielewicz, Artin Minaeian, Bharat Mocherla, Cynthia Murphy, Paul Murphy, Hirotaka Nagashima, Anil Nair, Malini Nair, John Nardandrea, Marshall Nash, Ziad Nasreddine, Yoshihiko Nishida, Jeffrey Norton, Lazaro Nunez, Jun Ochiai, Takuya Ohkubo, Yasuyuki Okamura, Eugene Okorie, Esteban Olivera, John O'mahony, Omid Omidvar, Desiree Ortiz-Cruz, Alexander Osowa, Michelle Papka, Alicia Parker, Paayal Patel, Ashok Patel, Meenakshi Patel, Claude Patry, Elizabeth Peckham, Michael Pfeffer, Alison Pietras, Michael Plopper, Anton Porsteinsson, Raphael Poulin Robitaille, Niels Prins, Orlando Puente, Marcin Ratajczak, Margaret Rhee, Angela Ritter, Ramon Rodriguez, Lilia Rodriguez Ables, Julio Rojas, Jeffrey Ross, Paule Royer, Jay Rubin, David Russell, Sterre Malou Rutgers, Stephanie Rutrick, Martin Sadowski, Beth Safirstein, Takafumi Sagisaka, Douglas Scharre, Lon Schneider, Curtis Schreiber, Michael Schrift, Paul Schulz, Harvey Schwartz, Julie Schwartzbard, John Scott, Lissette Selem, Pramod Sethi, Sharon Sha, Kenneth Sharlin, Sanjiv Sharma, Thomas Shiovitz, Rajinder Shiwach, Martin Sladek, Bart Sloan, Amanda Smith, Paul Solomon, Ehab Sorial, Evelio Sosa, Mary Stedman, Susan Steen, Lee Stein, Arkadiy Stolyar, John Stoukides, Shinji Sudoh, James Sutton, Junaid Syed, Kinga Szigeti, Hisatsugu Tachibana, Yuichi Takahashi, Amane Tateno, James Dale Taylor, Kelly Taylor, Oleg Tcheremissine, Adly Thebaud, Stephen Thein, Louise Thurman, Steven Toenjes, Hiromasa Toji, Misaki Toma, Duc Tran, Pilar Trueba, Masashi Tsujimoto, Raymond Turner, Akiyoshi Uchiyama, Dorota Ussorowska, Sanjeev Vaishnavi, Elena Valor, Joel Vandersluis, Alberto Vasquez, Juan Velez, Cherian Verghese, Klaudia Vodickova-borzova, David Watson, David Weidman, David Weisman, Alexander White, Katherine Willingham, Izabela Winkel, Paul Winner, Jaron Winston, Adam Wolff, Hideo Yagi, Hideki Yamamoto, Sanjay Yathiraj, Yasumasa Yoshiyama, Marzena Zboch
Journal: JAMA (2023)

Importance There are limited efficacious treatments for Alzheimer disease. Objective To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P &amp;amp;lt; .001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P &amp;amp;lt; .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P &amp;amp;lt; .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P &amp;amp;lt; .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration ClinicalTrials.gov Identifier: NCT04437511